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. 2021 Mar 1;131(5):e140453. doi: 10.1172/JCI140453

Figure 10. Three-hit model for the pathogenesis of PLA2R1-associated pMN.

Figure 10

Through as yet unidentified triggers, IgG4-predominant immunization against PLA2R1 is induced. An alteration of glycosylation allows these antibodies, when bound to their target antigen, to bind MBL and to activate the lectin complement pathway. Complement activation leads to assembly of the membrane attack complex (MAC) and C3a and C5a generation. A third hit, increased C3aR1 and C5aR1 expression on podocytes, facilitates C3aR1 and C5aR1 signaling, which decreases cellular cAMP levels. C3aR1/C5aR1 signaling and MAC insertion converge in the proteolysis of synaptopodin, NEPH1, and dynamin.